Iodinated esters of substituted benzoic acids and preparation thereof



United States Patent Filed Apr. 17, 1957,3e1. N0. 653,289

This invention relates to iodinated esters of substituted benzoic acids,and in particular it is concerned with hydroxyalkyl esters of3-acylamidoor 3,5-diacylamido-2, 4,6-triiodobenzoic acids having theformula R NHR wherein R is a lower-alkyl group having at least twocarbon atoms and substituted by from one to three hydroxy groups, saidhydroxy groups being on different carbon atoms and at least two carbonatoms removed from the canboxy group, R is a lower-alk'anoyl orhydroxy-l'oweralkanoyl radical, and R is a hydrogen atom or an amino,lower-lalkanoylamino or hydroxy-lower-alkanoylamino radical. Theinvention also relates to the process for preparing these compounds.

My new compounds are useful as X-ray contrast agents and areparticularly valuable for visualizing the bronchial tree bronchography),land for hepatolienography (visualization of the liver and spleen). Forbronchography these compounds can be introduced into the lungs either asa finely divided dust or in an aqueous suspension prepared by the aid ofemulsifying agents such as. carboxymethylcellulose,polyvinylpy-rrolidone, dextran and the like, for the purpose ofdelineating the morphology of the bronchial tree.

For hepatolienography the compounds are administered intravenously inthe form of an aqueous suspension of very finely divided particles.

The ethyl ester of 3-acetamiclo-2,4,6-triiodobenzoic acid is known. Ithas an oral toxicity in mice (LD of 78 grams per kilogram of bodyweight, and manifestations of systemic intoxication were observed atdoses as low as g./kg. as follows: intense hyperexoitability, tonicclonic convulsions, saliva-tion and respiratory depression. Thiscompound cannot safely be used as a bronchographic or hepatolienographicagent because of the large quantitles of material which must be used inthe procedures. Surprisingly, it has been found that the presence ofhydroxy groups in the alkyl ester moiety markedly decreases thetoxicity. The compounds of the invention possess oral LD values greaterthan 12 g./kg. and at this dose level exhibit no evidence of systemictoxicity.

The hydroxyalkyl esters of the present invention are superior to thecorresponding alkyl esters for the purpose of bronchography in that alesser quantity of emulsifying agent or detergent is needed to preparestable aqueous suspensions, thereby minimizing any tendency for thesuspension to produce alveolar flooding (chemical pneumonia) wheninstilled into the bronchi.

In the above general formula I, R represents a loweralkyl group,straight or branched, having from two to about six carbon atoms andsubstituted by from one to three hydroxy groups, said hydroxy groupsbeing on different carbon atoms and at least two carbon atoms removedfrom the carboxy group; in other Words, the carbon atom adjacent to thecarboxyl group is always unsubstituted. This restriction of theplacement of the hydroxy groups eliminates the hemiacetel typederivatives which would result from having a hydroxy group on the carbonatom attached to the carboxy group. The group R thus includes suchgroups as Z-hydroxyethyl, 3-hydroxypropyl, 2,3 dihydroxypropyl, 2,2dihydroxyisopropyl, 4-hydroxybutyl, 2,3,4 trihydroxyoutyl,S-hydroxypentyl, 6ihydroxyhexyl, and the like. i

In the above general formula I, R represents a lowerallcanoyl orhydroxylower-allcanoyl radical. The loweralkanoyl radicals are 'acylradicals derived from lower fatty acids having from one to about eightcarbon atoms; thus, lowcr-alkanoyl includes such groups as formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, caproyl,isocaproyl, heptanoyl and octanoyl. The hydroxy-lower-alkanoyl radicalsare the same radicals substituted by a hydroxy group.

In the above general cfionmula I, R represents a hydrogen atom or anamino, lower-allcanoylamino or hydroxylower-alkanoylamino radical. Thelower-alkanoyl and hydroxy-lower-alkanoyl radicals of R are the same asdefined and exemplified above for R, although in any given compound thealkanoyl groups of R and R" can be the same or different.

The compounds of the invention are prepared by heating an alkali metalsalt of an acid having the formula cool-r I II with the appropriatehalohydrin or epoxide. The halohydrin is of the formula XR where X ishalogen, preferably chlorine, bromine or iodine. The epoxide is onewhich yields the group R upon cleavage of the oxide ring by addition ofthe carbonyl group of the acid II.

The reaction between the alkali metal salt of the io din ated acid IIand a halohydrin is carried out by heating said salt and said halohydrinin approximately equimolar quantities in a reaction medium, inert underthe conditions of the reaction, at a temperature between 50 C. and C. Amatathesis reaction takes place in which an ester is produced betweenthe acid and hydrox alkyl moieties, an alkali metal halide being formedas a byproduct.

The reaction between the alkali metal salt of the acid II and an epoxideis carried out by contacting said salt and at least an equimolarquantity of said epoxide in an inert reaction, medium. The reactiontakes place Without application of heat. It is necessary only that asmall fraction of the acid II be in the form of its alkali metal saltsince the alkalinity of the mixture is not altered during the course ofthe reaction as in the case of the halohydrin which in eilect bringsabout a neutralization. Tlhe reaction with the epoxide is an additionreaction involving the opening of the epoxide ring.

The intermediate acids II are a known class of compounds; Larsen et al.I. Am. Chem. Soc. 78, 3210-6 (1956), and Wallingford US Patent2,611,786.

The structure of the compounds of the invention was established by themode of synthesis and by chemical analysis. The conversion of acidic toneutral substances indicated that reaction had taken place at the siteof the carboxyl group.

The following examples will further illustrate the invention withoutlimiting the latter thereby.

EXAMPLE 1 Z-Hydroxyethyl 3,5-Diacetaminfo-2,4,6-Triiodobenzoate [1; R isCH CH OH, R is COCH R" is CH CONH] A mixture of 127.2 g. (0.20 mole) ofsodium 3,5- diacetamido-2,4,6-triiodobenzoate and 30 g. (17 ml., 0.24

mole) of ethylene bromohydrin in 350 ml. of dimethylformamide Was heatedon a steam bath for six and one- (3 quarter hours. The mixture wasdiluted to 800 ml. with hot water and filtered while hot. Upon coolingthe filtrate a solid separated which was collected by filtration,stirred with 600 ml. of dilute sodium hydroxide solution and againcollected by filtration. The solid product was Washed with water anddried at 40 C. for seventy-two hours, giving 103 g. of 2-hydroxyethyl3,5-diacetamido- 2,4,6-triiodobenzoate, M.P. 265265.5 C. (dec.) (corn).

Analysis.Calcd. for C13H13I3N2O5: C, H, I, 57.9. Found: C, 23.73; H,2.00; I, 58.0.

By replacement of the ethylene bromohydrin in the preceding preparationby a molar equivalent amount of 2,2,2-tris (hydroxymethyl ethyl bromideI-methyl-Z-hydroxyethyl chloride, 4 hydroxybutyl bromide, or6-hydroxyhexyl bromide, there can be obtained, respectively,2,2,2-tris(hydroxymethyl)ethyl 3,5 diacetamido-2,4,fi-triiodobenzoate[1; R is CH C(CH OH) R is COCH R is CH CONH], l-methyl-Z-hydroxyethyl3,5- diacetamido-2,4,6-triiodobenzoate [I; R is CH(CH )CH OH R is COCH Ris CH CONHJ, 4-hydroxybutyl 3,5- diacetamido-2,4,6-triiodobenzoate [I; Ris CH CH CH OH R is COCH R" is CH CONH], or 6-hydroxyhexyl 3,5-diacetamido-2,4,6-triiodobenzoate [I; R is CH (CH CH OH R is COCH R isCH CONH].

By replacement of the sodium 3,5-diacetamido-2,4,6- triiodobenzoate inthe preceding preparation by a molar equivalent amount of sodium3-acetamido-5-formamido- 2,4,6-triiodobenzoate, sodium3,5-dipropionarnido-2,4,6- triiodobenzoate, sodium 3 acetamido-Soctanoylamino- 2,4,6-triiodobenzoate, sodium 3,5-dicaproylamino-2,4,6-triiodobenzoate, sodium 3-acetamido-S-hydroxyacetamido-2,4,6-triiodobenzoate, sodium 3-formamido-2,4,6-triiod0- benzoate,sodium 3-acetamido-5-amino-2,4,6-trii0dobenzoate, or sodium3-caproylamino-2,4,6-triiodobenzoate, there can be obtained,respectively, 2-hydroxyethyl 3-acetamido-5-formamido-2,4,6-triiodobenzoate [I; R is CH CH OH, R is COCH R" isHCONH], 2-hydroxyethyl 3,5-dipropionamido-2,4,6-triiodobenzoate [1; R isCH CH OH, R is COCH CH R" is CH CH CONH], 2-hydroxyethyl3-acetamido-S-octanoylamino-2,4,6-triiodobenzoate [I; R is CH CH OH, Ris COCH R" is CH (CH CONH], 2 hydroxyethyl3,5-dicaproylamino-2,4,6-triiodobenzoate [I; R is CH CH OH, R is CO(CHCI-I R is 2 hydroxyethyl 3-acetamido-5-hydroxyacetamido-2,4,6-triiodobenzoate [I; R is CH CH OH, R is COCH R is HOCH CONH],2-hydroxyethyl 3-formamido-2,4,6-triiodobenzoate [I; R is CH CH OH, R isCOH, R is H], 2-hydroxyethyl 3-acetamido-5-amino-2,4,6-triiodobenzoate[1; R is CH CH OH, R is COCH R is NH or 2-hydroxyethyl3-caproylamino-2,4,6-triiodobenzoate [I; R is CH CH OH, R is CO(CH CH Ris H].

EXAMPLE 2 2,3-Dihydr0xypr0pyl 3,5-Diacetamid0-2,4,6-

T riiodobenzoate [I; R is CH CH(OH)CH OH, R is COCH R is CH CONH] Amixture of 127.2 g. (0.20 mole) of sodium 3,5-diacetamido-2,4,6-triiod0benzoate and ml. of 2,3-dihydroxy propyl chloride in150 ml. of dimethylformarnide was refluxed for eight hours. The mixturewas filtered and the filtrate was concentrated in vacuo. The residue wastreated repeatedly with n-butanol and concentrated to remove water. Thedried residue was taken up in methanol, and the solution was filteredand concentrated to a small volume. The product was collected byfiltration, washed with cold methanol and acetone, recrystallized frommethanol and dried at 100 C. for four days, giving 2,3 dihydroxypropyl3,5-diacetamido-2,4,G-triiodobcnzoate, M.P. 239248.5 C. (dec.)(corr.).Analysis.-Calcd. fOl' C14H15I3N206: C, H, N, 4.07; O, 13.95; I, 55.3.Found: C, 24.77; H, 2.38; N, 4.07; O, 13.60; I, 55.0.

EXAMPLE 3 2,3-Dilzydr0xypropyl 3-Acetamid0-2,4,6-Trii0d0benz0alc [1; Ris CH CH(OH)CH OH, R is COCH R is H] A mixture of 53 g. (0.091 mole) ofsodium 3-acetamido-2,4,6-triiodobenzoate and 10 ml. of2,3-dihydroxypropyl chloride in ml. of dimethylformamide was refluxed135 C.) for six hours. The reaction mixture was filtered, the filtrateconcentrated in vacuo, and water was added to the residue. The solidproduct was collected by filtration, air dried, and recrystallized fromisopropyl alcohol containing a small amount of methanol, giving 42 g.,M.P. 165-200 C. The product was further purified by stirring with dilutesodium hydroxide, filtering, washing with water and recrystallizing froma methanolisopropyl alcohol mixture, giving 35 g. of 2,3-dihydroxypropyl3-acetamido-2,4,6 triiodobenzoate, M.P. 162166 C. (corn).

Analysis.Calcd. for C H I NO C, 22.84; H, 1.92;

I, 60.3. Found: C, 22.61; H, 1.91; I, 60.8.

EXAMPLE 4 Z-Hydroxyelhyl 3-Acetamid0-5-Hydr0xyacetamid0-2,4,6-

Triiodobenzoate [1; R is CH CH OH, R is COCH R" is HOCH CONH] 3Acetamido-S-hydroxyacetamido-2,4,6-triiodobenzoic acid (22.5 g., 0.036mole), 1.9 g. (0.018 mole) of sodium carbonate and 2.8 ml. (0.04 mole)of ethylene bromohydrin were added to 40 ml. of dimethylformamide, andthe mixture was heated for fourteen hours on a steam bath. The reactionmixture was concentrated to dryness in vacuo, and ml. of water andsufiicient 10% sodium hydroxide solution to make the mixture weaklybasic were added. The mixture was heated to boiling, activated charcoalwas added for decolorizing purposes, and the mixture was filtered. Fromthe filtrate upon cooling there separated 19 g. of product which whenrecrystallized from 240 ml. of water gave 16 g. of Z-hydroxyethyl3-acetamido-S-hydroxyacetamido 2,4,6-triiodobenzoate, M.P. 248 C.(dec.)(corr.).

Analysis.Calcd. for C H I N O C, 23.10; H, 1.93; N, 4.16; I, 56.5.Found: C, 23.15; H, 2.19; N, 4.10; I, 56.3.

EXAMPLE 5 Z-Hydroxyethyl 3-Acetamid0-2,4,o-Triiodobenzoate [1; R is CHCH OH, R is COCH R" is H] A mixture of 15 g. (0.026 mole) of sodium3-acetamido 2,4,6-triiodobenzoate and 4.1 g. (0.032 mole) of ethylenebrornohydrin in 45 ml. of dimethylformamide was heated on a steam bathfor seven and one-half hours. The reaction mixture was concentrated invacuo, and the residue was recrystallized first from 50 ml. of isopropylalcohol and then from methyl isobutyl ketone, giving Z-hydroxyethyl3-acetamido-2,4,6-triiodobenzoate, M.P. 184-186" C. (corn).

Analysis.-Calcd. for C H I NO C, 21.98; H, 1.68; I, 6.34. Found: C,22.25; H, 2.08; I, 63.3.

EXAMPLE 6 Z-Hydroxypropyl 3,5-Diacetamido-2,4,6-Triiodobelzzoate [I; Ris CH CH(OH)CH R is COOH R" is CH CONH] To 127.2 g. (0.20 mole) ofsodium 3,5-diacetamido- 2,4,6-triiodobenzoate in 500 ml. of water wasadded 15 ml. of concentrated hydrochloric acid (suificient to 75liberate 90% of the free acid), and then was added 30 g. of1,2-propylene oxide. The mixture was stirred at room temperature fortwenty hours, and the solid product was collected by filtration, washedwith water, recrystallized from aqueous dimethylformamide and dried,giving 35.7 g. of 2-hydroxypropyl 3,5-diacetamido-2,4,6-triiodobenzoate, M.P. 264.5 C. (dec.) (corr.).

Analysis.-Calcd. for C H I N O N, 4.17; I, 56.6. Found: N, 4.12; I,55.9.

By replacement of the propylene oxide in the preceeding preparation by amolar equivalent amount of ethylene oxide or 2-methyl-1,2-propyleneoxide, there can be obtained, respectively, Z-hydroxyethyl3,5-diacetamido- 2,4,6-triiodobenzoate [I; R is CH CH OH, R is COCH R isCH CONH], or Z-methyl-Z-hydroxypropyl 3,5-

diacetamido-2,4,6-triiodobenzoate [I; R is CH C(OH) (CI-I9 R is COCH Ris CH CONH].

I claim: 1. A compound having the formula C O O R R NHR wherein R is alower-alkyl group having at least two carbon atoms and substituted byfrom one to three hydroxy groups, said hydroxy groups being on difierentcarbon atoms and at least two carbon atoms removed from the carboxygroup, R is a member of the group consisting of loWer-alkanoyl andhydroxy-lower-alkanoyl radicals, and R is a member of the groupconsisting of hydrogen, amino, lower-alkanoylamino andhydroxylower-alkanoylamino radicals.

2. A compound having the formula COOR NHR

wherein R is a lower-alkyl group having at least two carbon atoms andsubstituted by from one to three hydroxy groups, said hydroxy groupsbeing on difierent car bon atoms and at least two carbon atoms removedfrom the carboxy group, and R is a lower-alkanoyl group.

3. A compound having the formula OOOR 6 wherein R is a lower-alkyl grouphaving at least two carbon atoms and substituted by from one to threehydroxy groups, said hydroxy groups being on different carbon atoms andat least two carbon atoms removed from the carboxy group, and R and Rare loweralkanoyl groups.

4. A compound having the formula COOR NHCOOH:

wherein R is a lower-alkyl group having at least two carbon atoms andsusbtituted by from one to three hydroxy groups, said hydroxy groupsbeing on different carbon atoms and at least two carbon atoms removedfrom the carboxy group.

5. A compound having the formula COOR OHaCONH NHCOOH:

3,5-diacetamido-2,4,6-triiodoben- References Cited in the file of thispatent UNITED STATES PATENTS 1,022,645 Taub Apr. 9, 1912 2,561,468 GuestJuly 24, 1951 2,611,786 Wallingford Sept. 23, 1952 2,776,241 Priewe etal. Jan. 1, 1957 OTHER REFERENCES Larsen et al., J. Am. Chem. Soc., 7 8,3210-6 (1956).

1. A COMPOUND HAVING THE FORMULA